A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity

Vincent Lombardi, Philippe Stock, Abinav K. Singh, Jerome Kerzerho, Wen Yang, Barbara A. Sullivan, Xiangming Li, Takayuki Shiratsuchi, Nathan E. Hnatiuk, Amy R. Howell, Karl O.A. Yu, Steven A. Porcelli, Moriya Tsuji, Mitchell Kronenberg, S. Brian Wilson, Omid Akbari

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyper-reactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidylethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of a-galactosylceramide (α-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to α-GalCer and competes with α-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the α-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.

Original languageEnglish (US)
Pages (from-to)2107-2115
Number of pages9
JournalJournal of Immunology
Volume184
Issue number4
DOIs
StatePublished - Feb 15 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity'. Together they form a unique fingerprint.

  • Cite this

    Lombardi, V., Stock, P., Singh, A. K., Kerzerho, J., Yang, W., Sullivan, B. A., Li, X., Shiratsuchi, T., Hnatiuk, N. E., Howell, A. R., Yu, K. O. A., Porcelli, S. A., Tsuji, M., Kronenberg, M., Wilson, S. B., & Akbari, O. (2010). A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity. Journal of Immunology, 184(4), 2107-2115. https://doi.org/10.4049/jimmunol.0901208